On the surprising correlation of apparently unrelated facts or findings. The demonstration of a previously unknown relationship between the DIC and enhanced bleeding tendency of liver failure and the release of endotoxin by the gut.
Effects of Endotoxin Shock on the Clotting Mechanism of Dogs
Study Of Fibrinogen Turnover Rates After Total Hepatecomy Dogs
Selective Phagocytosis: A New Concept in Protein Catabolism
On the In Vivo Clearance and Detoxification of Endotoxin by Lung and Liver
Antibodies And Intravascular Clotting In Liver Cirrhosis
As was mentioned above, this letter to the Lancet was the first report that linked the DIC observed in liver failure (both in the anhepatic dog and in liver cirrhosis in man, but also during the anhepatic stage of an an orthotopic liver transplantation) to the normal release of endotoxin by the gut.
Although Orloff et al had failed to find any microorganisms in human portal vein blood (in stark contrast to his finding in the dog(1), Prytz et al, and subsequently many others, demonstrated endotoxin in the portal vein blood of patients both with and without liver disease (2). They confirmed the beneficial effect of heparin in preventing the DIC observed in patients with liver cirrhosis*. These findings lead Souhami to conclude that antigens (such as endotoxins) that bypass the liver, are taken up by extra-hepatic phagocytes (in spleen and bone marrow) that induce an enhanced immune response, to explain the noted hypergammaglobulinaemia of liver cirrhosis (3).
Many related subsequent studies fomented such a wide interest that they lead, directly or indirectly, to three major international conferences on endotoxin and the RES, the first one in Vienna (European Immuno-Symposium on Endotoxin, Sept 27-30, 1973), the next in Copenhagen (Workshop on Endotoxin and Liver Disease, Aug 25-28, 1976) and subsequently also one in Wurzburg (The International Biomedical Symposium on the Reticulo-endothelial System and the Pathogenesis of Liver Disease, Sept 29-Oct 1,1979).
This previously unsuspected relationship was subsequently confirmed by a host of investigators whose reports corroborated the findings of our initial hepatectomy paper (1964) and its subsequent (1972) conformation (4). Whether endotoxin, besides causing the hypercoagulablity of blood, also contributes to other symptoms that patients with liver cirrhosis exhibit, such as the typical vascular lesions, the ascites, and possibly some of the pulmonary and neurological manifestations remained to be established.
Because of the enhanced bleeding in the first patient who, Febr 1969 had an orthotopic liver transplantation at Memorial Hospital, across the street from the New York Hospital, when its surgeons reported a blood loss of 52 Units (5), we at New York Hospital chose three months later ( May 19, 1969) to do a heterotopic liver transplantation in our first case and barely lost any blood at all (6).
Twenty five years later (in 1989), Starzl’s group reported that during an orthotopic liver transplantation the patient’s blood endotoxin levels -- due to its systemic effect during the anhepatic state, in addition to the replacement of the patient’s own liver by an organ with a compromised RES -- may be a significant determining factor in the recipient’s ultimate clinical outcome (7).
Ref.
1) Orloff M J Peskin GW Ellis H: “A Bacteriologic Study of Human Portal Blood. Implications regarding hepatic ischemia in man.” Ann Surg 148 (1958) 738.
2) Prytz H, Holst-Christensen J, et al. (1976) Portal and Systemic Endotoxemia in Patients without Liver Disease and Systemic Endotoxemia in Patients with Cirrhosis. Scand J Gastroent . 11: 875 ; Jacob AI, Goldberg PK, Bloom N et al(1977) Endotoxin and Bacteria in Portal Blood. Gastroenterology 72: 1268.
* Previously, Carlo Grosso had shown the beneficial effect of EACA on the enhanced fibrinolytic activity in patients with liver cirrhosis, in: Grossi CE Moreno AH Rousselot: “Studies on the spontaneous fibrinolytic activity in patients with cirrhosis of the liver and its inhibition by EACA,” Ann Surg 153 (1961): 383.
3) Souhami RL (1972) Bacterial Antibodies in Liver Disease, Lancet 1: 384.
4) Tarao K, So K, Moiroi T et al: “Detection of endotoxin in plasma and ascites fluid of patients with cirrhosis: its clinical significance”. Gastroenterology 73 (1977), 539. Jacob AI, Goldberg PK,, Bloom N et al: “Edotoxin and bacteria in portal vein blood”, Gastroenterology 72 (1977) 1268. Wilkinson SP, Moodie H, Stamatahu JD et al: “Endotoxemia and renal failure in cirrhosis and obstructive jaundice”. Brit Med J 2 (1976): 1415, Colman M Filayson N et al: “Fibrinogen survival in cirrhosis, improvement by ‘low-dose” heparin.” Ann Int Med 83 (1975): 79. Clemente C, Bosch J et al: “Functional renal failure and hemorrhagic gastritis associated with endotoxemia in cirrhosis”. Gut 18 (1977): 556, Prytz H, Hoest-Christenson J et al: “Portal liver disease and systemic endotoxemia in patients with cirrhosis”. Scand J Gastroenetrol 11 (1976) 857, Moschl P, Lubec G, Keller A Kreuzer W: Is endotoxin containing ascites contraindication for peritoneo-venous shunt?” IRS Med Sci 6 (1978) 454, Van Vliet ACM, Maas HCM, Wilson JHP: letter in Gastroenterology 80: (1981) 419, Cooperstock MS, Tucker RP, Baublis JV: “Possible pathogenic role of endotoxin in Reye’s Syndrome”, Lancet 1 (1975): 1272, Liehr HGrun M “Endotoxemia in liver disease.” in The RES and the pathogenesis of liver disease. Ed. Elsevier (1980) 325. Guarner C Soriano G Toams A et al: “Increase serum nitrate and nitrate levels in patients with cirrhosis: relationship to endotoxemia” Hepatology 18:(1993) 1139, Liehr H Jacob AI: “Endotoxin and renal failure in liver disease”. In M Epstein (ed) The kidney in liver disease ed. 2. New York, Elsevier Biomedical 1983 p 535. Brussino L Bucca C Morello M Scappaticci E Nauro M Rolla G: “Effect of dyspnoea and hypoxaemia of inhaled N-nitro-L-arginine methyl ester in hepatopulmonary syndrome”. Lancet 362 (1999): 43, C Goulis J Patch D Burroughs AK : “Bacterial infection in the pathogenesis of variceal bleeding.” Lancet 353 (1999) 139, Violi F et al: “Associaition between low grade DIC and endotoxemia in patients with liver cirrhosis”. Gastroenterology 109 (1995), Violi F Basili S Ferro D et al, “Association between high values of D-dimer and tissue plasminogen activator activity and first gastrointestinal bleeding in cirrhotic patients”, Thromb Haemost 76 (1996) 177 and many, many others. The earliest publication of the subject I could find was by R L Whipple, JF Harris: “B Coli septicemia in Laennec’s cirrhosis of the liver.” Ann Int Med 33:(1950): 462.
5) Fortner et al: Ann Surg 172 (1970) 23,
6) American Cancer Society and U.S. National Health, ACS/NIH organ transplantation registry, JAMA 217 (1971); 1520
7) Yokoyama I, Todo S, Miyata T et al: “Endotoxemia and human liver transplantation.” Transpl Proc 21 (1989): 3833, Miyata T Todo S Imventarza O Furukawa H Starzl TE: “Endogenous endotoxemia during orthotopic liver transplantaion in dogs.” Transpl Proc 21(1989): 386. Miyata T, Todo S, et al: “Endotoxemia, pulmonary complications, and thrombocytopenia in liver transplantation,” Lancet 1 (1989):189, Yokoyama I et al: “Endotoxemia is associated with renal dysfunction in liver transplantation during the first postoperative week “ Hepato-gastro-enterology 42 (1995): 205.
Although Orloff et al had failed to find any microorganisms in human portal vein blood (in stark contrast to his finding in the dog(1), Prytz et al, and subsequently many others, demonstrated endotoxin in the portal vein blood of patients both with and without liver disease (2). They confirmed the beneficial effect of heparin in preventing the DIC observed in patients with liver cirrhosis*. These findings lead Souhami to conclude that antigens (such as endotoxins) that bypass the liver, are taken up by extra-hepatic phagocytes (in spleen and bone marrow) that induce an enhanced immune response, to explain the noted hypergammaglobulinaemia of liver cirrhosis (3).
Many related subsequent studies fomented such a wide interest that they lead, directly or indirectly, to three major international conferences on endotoxin and the RES, the first one in Vienna (European Immuno-Symposium on Endotoxin, Sept 27-30, 1973), the next in Copenhagen (Workshop on Endotoxin and Liver Disease, Aug 25-28, 1976) and subsequently also one in Wurzburg (The International Biomedical Symposium on the Reticulo-endothelial System and the Pathogenesis of Liver Disease, Sept 29-Oct 1,1979).
This previously unsuspected relationship was subsequently confirmed by a host of investigators whose reports corroborated the findings of our initial hepatectomy paper (1964) and its subsequent (1972) conformation (4). Whether endotoxin, besides causing the hypercoagulablity of blood, also contributes to other symptoms that patients with liver cirrhosis exhibit, such as the typical vascular lesions, the ascites, and possibly some of the pulmonary and neurological manifestations remained to be established.
Because of the enhanced bleeding in the first patient who, Febr 1969 had an orthotopic liver transplantation at Memorial Hospital, across the street from the New York Hospital, when its surgeons reported a blood loss of 52 Units (5), we at New York Hospital chose three months later ( May 19, 1969) to do a heterotopic liver transplantation in our first case and barely lost any blood at all (6).
Twenty five years later (in 1989), Starzl’s group reported that during an orthotopic liver transplantation the patient’s blood endotoxin levels -- due to its systemic effect during the anhepatic state, in addition to the replacement of the patient’s own liver by an organ with a compromised RES -- may be a significant determining factor in the recipient’s ultimate clinical outcome (7).
Ref.
1) Orloff M J Peskin GW Ellis H: “A Bacteriologic Study of Human Portal Blood. Implications regarding hepatic ischemia in man.” Ann Surg 148 (1958) 738.
2) Prytz H, Holst-Christensen J, et al. (1976) Portal and Systemic Endotoxemia in Patients without Liver Disease and Systemic Endotoxemia in Patients with Cirrhosis. Scand J Gastroent . 11: 875 ; Jacob AI, Goldberg PK, Bloom N et al(1977) Endotoxin and Bacteria in Portal Blood. Gastroenterology 72: 1268.
* Previously, Carlo Grosso had shown the beneficial effect of EACA on the enhanced fibrinolytic activity in patients with liver cirrhosis, in: Grossi CE Moreno AH Rousselot: “Studies on the spontaneous fibrinolytic activity in patients with cirrhosis of the liver and its inhibition by EACA,” Ann Surg 153 (1961): 383.
3) Souhami RL (1972) Bacterial Antibodies in Liver Disease, Lancet 1: 384.
4) Tarao K, So K, Moiroi T et al: “Detection of endotoxin in plasma and ascites fluid of patients with cirrhosis: its clinical significance”. Gastroenterology 73 (1977), 539. Jacob AI, Goldberg PK,, Bloom N et al: “Edotoxin and bacteria in portal vein blood”, Gastroenterology 72 (1977) 1268. Wilkinson SP, Moodie H, Stamatahu JD et al: “Endotoxemia and renal failure in cirrhosis and obstructive jaundice”. Brit Med J 2 (1976): 1415, Colman M Filayson N et al: “Fibrinogen survival in cirrhosis, improvement by ‘low-dose” heparin.” Ann Int Med 83 (1975): 79. Clemente C, Bosch J et al: “Functional renal failure and hemorrhagic gastritis associated with endotoxemia in cirrhosis”. Gut 18 (1977): 556, Prytz H, Hoest-Christenson J et al: “Portal liver disease and systemic endotoxemia in patients with cirrhosis”. Scand J Gastroenetrol 11 (1976) 857, Moschl P, Lubec G, Keller A Kreuzer W: Is endotoxin containing ascites contraindication for peritoneo-venous shunt?” IRS Med Sci 6 (1978) 454, Van Vliet ACM, Maas HCM, Wilson JHP: letter in Gastroenterology 80: (1981) 419, Cooperstock MS, Tucker RP, Baublis JV: “Possible pathogenic role of endotoxin in Reye’s Syndrome”, Lancet 1 (1975): 1272, Liehr HGrun M “Endotoxemia in liver disease.” in The RES and the pathogenesis of liver disease. Ed. Elsevier (1980) 325. Guarner C Soriano G Toams A et al: “Increase serum nitrate and nitrate levels in patients with cirrhosis: relationship to endotoxemia” Hepatology 18:(1993) 1139, Liehr H Jacob AI: “Endotoxin and renal failure in liver disease”. In M Epstein (ed) The kidney in liver disease ed. 2. New York, Elsevier Biomedical 1983 p 535. Brussino L Bucca C Morello M Scappaticci E Nauro M Rolla G: “Effect of dyspnoea and hypoxaemia of inhaled N-nitro-L-arginine methyl ester in hepatopulmonary syndrome”. Lancet 362 (1999): 43, C Goulis J Patch D Burroughs AK : “Bacterial infection in the pathogenesis of variceal bleeding.” Lancet 353 (1999) 139, Violi F et al: “Associaition between low grade DIC and endotoxemia in patients with liver cirrhosis”. Gastroenterology 109 (1995), Violi F Basili S Ferro D et al, “Association between high values of D-dimer and tissue plasminogen activator activity and first gastrointestinal bleeding in cirrhotic patients”, Thromb Haemost 76 (1996) 177 and many, many others. The earliest publication of the subject I could find was by R L Whipple, JF Harris: “B Coli septicemia in Laennec’s cirrhosis of the liver.” Ann Int Med 33:(1950): 462.
5) Fortner et al: Ann Surg 172 (1970) 23,
6) American Cancer Society and U.S. National Health, ACS/NIH organ transplantation registry, JAMA 217 (1971); 1520
7) Yokoyama I, Todo S, Miyata T et al: “Endotoxemia and human liver transplantation.” Transpl Proc 21 (1989): 3833, Miyata T Todo S Imventarza O Furukawa H Starzl TE: “Endogenous endotoxemia during orthotopic liver transplantaion in dogs.” Transpl Proc 21(1989): 386. Miyata T, Todo S, et al: “Endotoxemia, pulmonary complications, and thrombocytopenia in liver transplantation,” Lancet 1 (1989):189, Yokoyama I et al: “Endotoxemia is associated with renal dysfunction in liver transplantation during the first postoperative week “ Hepato-gastro-enterology 42 (1995): 205.